Epithelial PIK3R1 (p85) and TP53 Regulate Survivin Expression during Adaptation to Ileocecal Resection.

Cohran V, Managlia E, Bradford EM, Goretsky T, Li T, Katzman RB, Cheresh P, Brown JB, Hawkins J, Liu SXL, De Plaen IG, Weitkamp JH, Helmrath M, Zhang Z, Barrett TA
Am J Pathol. 2016 186 (7): 1837-1846

PMID: 27157990 · PMCID: PMC4929398 · DOI:10.1016/j.ajpath.2016.03.008

Intestinal adaptation to small-bowel resection (SBR) after necrotizing enterocolitis expands absorptive surface areas and promotes enteral autonomy. Survivin increases proliferation and blunts apoptosis. The current study examines survivin in intestinal epithelial cells after ileocecal resection. Wild-type and epithelial Pik3r1 (p85α)-deficient mice underwent sham surgery or 30% resection. RNA and protein were isolated from small bowel to determine levels of β-catenin target gene expression, activated caspase-3, survivin, p85α, and Trp53. Healthy and post-resection human infant small-bowel sections were analyzed for survivin, Ki-67, and TP53 by immunohistochemistry. Five days after ileocecal resection, epithelial levels of survivin increased relative to sham-operated on mice, which correlated with reduced cleaved caspase-3, p85α, and Trp53. At baseline, p85α-deficient intestinal epithelial cells had less Trp53 and more survivin, and relative responses to resection were blunted compared with wild-type. In infant small bowel, survivin in transit amplifying cells increased 71% after SBR. Resection increased proliferation and decreased numbers of TP53-positive epithelial cells. Data suggest that ileocecal resection reduces p85α, which lowers TP53 activation and releases survivin promoter repression. The subsequent increase in survivin among transit amplifying cells promotes epithelial cell proliferation and lengthens crypts. These findings suggest that SBR reduces p85α and TP53, which increases survivin and intestinal epithelial cell expansion during therapeutic adaptation in patients with short bowel syndrome.

Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

MeSH Terms (22)

Adaptation, Physiological Animals Blotting, Western Class Ia Phosphatidylinositol 3-Kinase Digestive System Surgical Procedures Disease Models, Animal Enterocolitis, Necrotizing Extracellular Matrix Proteins Gene Expression Regulation Humans Immunohistochemistry Infant Infant, Newborn Inhibitor of Apoptosis Proteins Mice Mice, Inbred C57BL Phosphatidylinositol 3-Kinases Real-Time Polymerase Chain Reaction Repressor Proteins Short Bowel Syndrome Survivin Tumor Suppressor Protein p53

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